Good Laboratory Practices and Pesticide Regulation in Japan - ACS

Chapter 31

Good Laboratory Practices and Pesticide Regulation in Japan Fumihiko Ichinohe

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Agricultural Chemical Inspection Station, Ministry of Agriculture, Forestry and Fisheries, Tokyo 187, Japan

In Japan, the Agricultural Chemicals Regulation Law provides that "to obtain registration, applicants shall submit the test results concerning effectiveness, phytotoxicity, toxicity and persistence in crops and soil, etc., of each agricultural chemical." Most test guidelines for these studies follow the OECD Test Guidelines, and the rest of them are now considered to be harmonized with OECD guidelines. For toxicity studies, we notified applicants about the "Good Laboratory Practice Standards for Toxicological Studies on Agricultural Chemicals" and required them to comply with GLP standards for all study data generated. In accordance with the OECD Council Recommendation, we will gradually extend the scope of types of study data for the application of the GLP system after the establishment of domestic test guidelines. The GLP standards of Japan are almost similar to OECD GLP Principles and the GLPs of the US. Japan accepts the inspection results of the countries with whom Japan has concluded a bilateral arrangement.

GLP System for Agricultural Chemicals in Japan The GLP system is a very effective means to secure the reliability of study data. In June 1979, the US Food and Drug Administration (7) took the initiative in introducing this system for pharmaceutical products. In May 1981, the Organization for Economic Cooperation and Development (2) established principles to help individual countries bring their GLP standards up to an international level. Based on international trends, the Ministry of Agriculture, Forestry and Fisheries also had started considering the introduction of this system. On August 10, 1984, the Director-General of Agricultural Production Bureau issued the notice entitled "the GLP Standards for Toxicological Studies on Agricultural Chemicals" (5) which took effect on October 1, 1984. Since

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© 1999 A m e r i c a n C h e m i c a l Society

In International Pesticide Product Registration Requirements; Garner, W., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.

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then, the GLP system is applied only to toxicological study data. In establishing a GLP system for agricultural chemicals, the Ministry thoroughly considered other GLP systems and related information in Japan and abroad, such as actual situations at domestic testing laboratories, the GLP system for pharmaceutical products introduced by the Ministry of Health and Welfare, and the US GLP system and how those systems work. The Japanese GLP system is well harmonized with foreign countries. Bilateral Agreement Concerning GLP Systems. As many countries had introduced GLP systems, reliability of toxicological study data prepared in a foreign country could be secured, and those data could then be used for the registration application of agricultural chemicals. However, it is very difficult to verify the reliability of study data generated by laboratories in foreign countries with the way studies are conducted in Japan. Consequently, it is efficient to make bilateral agreements between the two countries concerned saying that each government confirms and assures that the laboratories involved comply with the GLP standards applied in the country. So far, Japan has made bilateral agreements with the four countries listed in Table I, and toxicological study data are now mutually accepted in those countries.

Table L Japan's Counterparts in Bilateral Agreements Date ofAgreement US Sept. 16, 1987 UK Oct. 7, 1987 Germany Feb. 16,1988 Switzerland Jan. 18, 1993

Japan also accepts toxicological study data prepared by laboratories in countries with whom Japan has not yet made an agreement. In those cases, the GLP standards of the country are required to comply with OECD GLP Principles (2), and GLP compliance by the laboratory for study data it generates should be certified by the appropriate authorities in the country. Mechanism of the GLP System. The purpose of the GLP system for agricultural chemicals is basically to confirm the reliability of individual data. In practice, a system of "the confirmation of GLP compliance" includes a method for inspecting the laboratory organization and its operation, as well as other related matters. Under this system, laboratories are required to apply every three years for an inspection under which the laboratory is checked to see if it has been operated in compliance with the GLP standards for the last three years. Laboratories preparing toxicological study data are required to undergo this inspection for the registration application of agricultural chemicals.


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Application for a Reliability Confirmation Inspection. Table II shows the number of applications submitted and inspections conducted for last 13 years, from 1984 (when the GLP system was introduced into Japan) until 1996. Roughly, some 40 domestic laboratories and 50 foreign laboratories have submitted inspection applications in each three-year period. Most of the foreign applications came from the four countries that have obtained bilateral agreements with Japan. Others came from laboratories in France, the Netherlands, and Italy.

Table IL Applications and Inspections for Confirmation of GLP Compliance Japan Overseas Year Applications Inspections Applications Inspections 1984 7 0 1 1 1985 21 0 9 11 1986 7 17 0 10 1997 6 0 10 12 1988 14 15 0 15 1989 12 20 0 8 1990 11 17 0 12 1991 19 0 18 14 1992 12 27 0 13 1993 11 0 9 11 1994 18 14 13 1 1995 14 0 27 11 1996 11 0 7 10

With the application, on-site inspections are carried out at domestic laboratories that have conducted toxicological studies for registration applications of agricultural chemicals within the last three years. During the interval of three years, some 35-40 laboratories undergo this inspection. For foreign laboratories, an inspection was conducted in 1994 in a U.S. laboratory in collaboration with the U.S. Environmental Protection Agency under the bilateral agreement. Future of the GLP System. The GLP system can be applied not only to toxicological studies but to other various studies. Some OECD countries have already applied the GLP system to studies other than toxicological studies, such as physical/chemical property studies. The scope of the studies under the GLP system will surely be expanded in Japan. Under such a global tide, the Ministry of Agriculture, Forestry and Fisheries (MAFF) now takes into consideration the expanding of the types of studies to which the GLP system will be applied in response to requests from foreign countries. MAFF will apply the GLP system to physical/chemical property studies and ecotoxicological


269 studies on aquatic organisms before long. In the future, this system will be applied to other various studies.


Pesticide Safety Evaluation in Japan Pesticides are agricultural chemicals that are used for the control of insects and fungi which injure agricultural crops and/or for the improvement and control of physiological functions in the plant. The ideal is that pesticides will be effective only against pests and will be harmless to people, useful animals and plants, and the environment. However, they have physiological properties that may show injurious effects to the latter. Therefore, when we deal with pesticides, we must pay appropriate attention to human health and environmental conservation. To this end, it is necessary to know exactly the properties of the pesticide in question in order to make a suitable safety evaluation. Safety Evaluation System. Of all chemicals, pesticides, as a group, have the most extensive safety and toxicological data bases. Safety evaluations are required for all pesticides prior to registration and marketing. These tests are designed to mimic the potential routes and conditions of exposure for man and the environment. According to the Agricultural Chemicals Regulation Law (4), no manufacturer or importer is allowed to provide a pesticide for sale on the domestic market in Japan unless registration has been granted by the Minister of Agriculture, Forestry and Fisheries. In the process of registration review, safety evaluation is strictly implemented. Procedures for Registration Application. For the registration application, the manufacturer or importer of agricultural chemicals makes an application by submitting a product registration application form, experimental data, and a sample of the product. These materials are submitted to the Minister of Agriculture, Forestry and Fisheries via the Director of the Agricultural Chemicals Inspection Station. Product Registration Application Form. This application form is based on supporting data that are described as specified below: • • • • • • •

• • •

Name and address of the applicant for registration Common name of the pesticide and its trade name Physical and chemical properties Name and content of active ingredients Name and content of other constituent Kind and material of containers or packs and net content Spectrum of pests (including weeds and rats) controlled by the products and the manner of application. For plant growth regulators, spectrum of crop and purpose of application. Mammalian toxicity and detoxication method Toxicity to aquatic organisms Flammability, explosiveness and skin irritability


270 • • •

Precautions necessary for storage and/or use Name and location of manufacturing plant Manufacturing process and names of the people in charge of manufacturing

Data Requirements. Listed below are the required studies for pesticide registration:


• •

•

Efficacy and phytotoxicity study - A phytotoxicity study is not only for target crops, but also for adjacent and/or subsequently raised crops. Toxicity study - Toxicological data requirements are described in Table III. The toxicity test must be conducted properly and impartially, otherwise safety evaluations are not secured with accuracy and reliability. These data should be produced in laboratories that are confirmed by the authorities as being in compliance with the GLP standards. Residue chemistry ~ 1) Residue remaining in the crop - Information on the amount, frequency and time of pesticide application and the results of tests on the level of residues persisting in the treated crop are required for pesticides for food use. Trials are conducted at more man two different Prefectures and samples are analyzed at more than two separate laboratories. A description of the analytical method also is required. 2) Retention in the soil - Information on the retention levels of the pesticides in soil is required. This study is conducted in the field and in pots.

• • • •

Physical and chemical properties of the active ingredients) Composition of the technical grade of the active ingredients) - Impurities have to be identified and quantified with the most advanced analytical techniques. Formulation - The kinds and contents of any inert ingredient in the formulation have to be made clear. Environmental impact on fish or other nontarget organisms including silkworms, bees, natural enemies and wild birds.

Review of the Data for Registration. Review is conducted by checking whether the results of the studies submitted in the application fall under the conditions laid down for withholding a registration. If they fall under even one of the registration withholding clauses, the applicant is required to amend the statement entered in the application form and/or to improve the product quality, otherwise the registration is withheld. The conditions for withholding registration are as follows: • •

False facts are found in application statement. Crops are damaged by the product that is used according to the directions given in the statement.


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Table ΠΙ. Toxicology Data Requirements for the Registration Application of Pesticides Substance Kind of Data Required General Use Pattern Test TGAI End-use Non-food Food Product Crop Crop (Acute toxicity study) Acute oral toxicity R R R R Acute dermal toxicity R R R R R R R Acute inhalation toxicity R R Ν Primary eye irritation R R Primary dermal irritation R R Ν R R Dermal sensitization Ν R R Ν R Acute delayed R R neurotoxicity (Subchronic toxicity study) Subchronic oral toxicity R R R Ν Subchronic dermal C Ν C C toxicity Subchronic inhalation C C C Ν toxicity Subchronic neurotoxicity C C C Ν (Long term toxicity study) Chronic toxicity R C R Ν Oncogenicity R R Ν C (Special toxicity study) Reproduction R C R Ν Teratogenicity R R R Ν Mutagenicity R R (Others) Metabolism R R Pharmacology R R "Technical grade of active ingredient R: Required C: Conditionally required N: Not required - : Not specified


a

-

-


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•

The product can do harm to man and livestock even if prescribed means are taken to avert such damage. • *In view of the persistence of residues in crops, the product contaminates crops and can do harm to man and livestock. • '"The product contaminates the soil and can do harm to man and livestock due to ingesting any crops that are raised in the contaminated soil. • *In view of its toxicity to aquatic animals and plants and its toxicity persistence, the product pollutes water to cause damage to them and can do serious harm. • *The product pollutes water in the water catchment area for public use and can do harm to man and livestock due to use of that water. • The trade name of the product can cause misunderstanding about the main components and/or their effectiveness. • The product is so inferior in efficacy that it should not be approved as an agricultural chemical. • For the product to which the official standard has been applied, it does not fit in with official standards and its efficacy is inferior to other products conforming to the standard. The criteria of the conditions from the asterisked items, above, are laid down and noticed by the Director-General of the Environmental Agency. The criteria make up the so-called "registration withholding limit", which is a kind of tolerance. In particular, concerning residues remaining in a food crop, all data on toxicity and residual persistence are strictly reviewed by the authorities concerned, and these limits for each pesticide ingredient are noticed for the food group under which crops for the registration application are assigned. At the Agricultural Chemicals Inspection Station, the registration application is under review to ascertain whether the residual level remaining in the crops exceeds the registration withholding limit when the product is applied with regard to the directions for use stated in the application form. Regarding the third condition, above, for safety in use, acute toxicities mainly are evaluated by the authorities concerned, and those evaluations are reflected in the registration review. Those registration applications, which passed this strict review, are set with proper application directions such as time, frequency, rate and protective clothing and then registered in the name of the Minister of Agriculture, Forestry and Fisheries. These items are indicated on the label of the container. Designation of Toxic Substances. Pesticide products, for which their acute toxicity is very important, are under review in the Ministry of Health and Welfare and are designated as poisonous or deleterious substances under the Poisonous and Deleterious Substances Control Law (5). Designated pesticides are then indicated to that effect in a statement on the label and are requested to be kept in a locked place. With regard to the safety of pesticides, we also have to examine other properties of these chemicals. Their properties include phytotoxicity; pollution to the environment, such as,rivers,lakes and sea; and injury to people and useful animals. With a view to averting such damage, many kinds of data must be submitted for the


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registration application and these are under strict review. Consequently, registrations are only granted under certain terms and conditions. Establishment of the Tolerance. Tolerances of pesticides constitute two groups. One group is composed of tolerances based on the Food Sanitation Law (6), which is called "the pesticide tolerance". The others are tolerances determined by the DirectorGeneral of the Environment Agency (7) to be based on the Agricultural Chemicals Regulation Law (4), which is called "the pesticide registration withholding limit". The latter tolerances are set up based on those that the former has not determined. The principle for setting up a tolerance is as follows: a tolerance is laid down within a range so that the total dietary exposure level does not exceed the ADI. The following formula gives the relationship between the tolerance and the ADI: / Average daily intake of \ = each food group (kg) χ tolerance (ppm) \

Estimated dietary exposure level (EDEL) mg

EDEL < ADI χ 50 mg/man The tolerance is, in principle, set up for each food group. If it is necessary to set up a tolerance for many food groups, the total dietary exposure is estimated from the sum of the intake by individual food groups, which should not exceed the ADI χ 50 mg/man. The amount of intake by food groups is derived from the Current Report of National Nutrients of the Ministry of Health and Welfare. Pesticide residue data are also taken into consideration. The tolerance is set up with a certain safety margin calculated from the residue level obtained from the data. The relationship between the tolerance and residue level is given in the following schematic: Tolerance > Maximum residue level > Average residue level On setting up tolerances, the estimated total dietary exposure is supposed to be based on the following assumptions and conditions: • • •

The pesticide is applied to all varieties of crops of each food group for which the tolerance is being set. The residue level remaining in the crops is equal to the tolerance. Any decrease of the residue level by washing, cooking and processing is not taken into consideration.

From these assumptions, the total dietary exposure level is estimated as being much more than the real intake level. The reasons are as follows:



274 To the first assumption, the varieties of the crop, for which registration is granted, do not all come under the food group, but only some part of it. Furthermore, the pesticide concerned is not necessarily the only one which is used on the crops, as some other pesticides might be applied to the same crops as well. To the second assumption, the average residue level is much less than the tolerance. To the third assumption, crops are, in general, washed, cooked and processed, thus removing much of the pesticide residues. Toward the end of promoting global trade of agricultural commodities, it is necessary to set up food and feed standards. F AO/WHO of the United Nations has jointly established the Codex Alimentarium Committee (CAC). Pesticide residues of food and livestock feed among the countries are covered by the Codex Committee of the Pesticide Residues (CCPR) who establish the Maximum Residue Limits (MRL) with the support of the Joint Meeting of Pesticide Residues (JMPR). Japanese tolerances are set up not to exceed the ADI so people do not get damaged at all, even though a person may get a daily intake of the pesticide residue over his lifespan. Meanwhile, MRLs of the CCPR are set up based on the Good Agricultural Practices (GAPs). MRLs are attributed to the level of the pesticide residues remaining in the agricultural products raised under the best control of cultivation with the application of the minimum amount of pesticide. Accordingly, MRLs are established apart from the ADI. In Japan, tolerances are directly established in view of human health, but MRLs are primarily set in view of the necessity of the pesticide for agricultural production. These MRLs seem to be separate from the levels of pesticide residue in food and feed that are related to human health. However, CCPR has conducted a total diet survey and/or market basket survey using residue of our agricultural chemicals and has confirmed the estimated total level of pesticide residue intake to be far below the ADI. Setting Up the Directions for Use. Residue levels are subject not only to weather conditions but also to many other factors, such as, the application time, frequency of application, rate, and methods, such as, top dressing or mixing in the soil. Accordingly, on the basis of data of pesticide residue levels in crops, the directions for use are set up in such a way that the residue levels do not exceed the tolerance. The directions include the applicable varieties of the crops, rate, time (the minimum number of days from the last application before harvest), frequency, and precautions for application, etc. These items are indicated on the label of the containers. Table IV shows some examples of setting up tolerances and directions for use of a registered pesticide that is applied to paddyriceand several crops from the group of fruits and fruiting vegetables. In this instance, the estimated total dietary exposure level is far less than the ADI χ 50. Aquatic Assessment - Risk Assessment/Risk Mitigation. Aquaticriskassessment is conducted in Japan from two aspects; 1) risk to human health via drinking water, and 2)riskto aquatic organisms.



275 Table IV. Example for Setting Up the Tolerances and Directions for Use Food Food Tolerance Estimated ADI χ 50 Maximum Direction for Use Factor (ppm) Dietary (mg/man) Residue Group Exposure Level (g) (MRLs) Level-mg (ppm) (TMDI) 2 times, Rice 203 1.7 1.015 14 days before harvest Large Fruits Class2

68

Fruiting Vegetables Class2

42

Total

10

0.340

2.1

Apple, 3 times, 7 days before harvest

0.420

3.2

Cucumber, 2 times, 1 day before harvest

1.775

10

Assessment and Mitigation of Risk to Human Health via Drinking Water. The main exposure route is run-off from paddy water. Spray drift is taken into account qualitatively, but the calculation of the Predicted Environmental Concentration (PEC) is not done. To assess risk to human health caused by a pesticide via run-off, it is necessary for applicants to submit a dissipation study of the pesticide in water from two small scale paddy fields with different soil types. Normally, that is the 7 to 14 day dissipation study in which 7 days' average concentration level of the pesticide is obtained. The 150 days' average concentration level as PEC is estimated from seven days' average concentration level. The reason for taking a 150 days' average concentration level is that the usual time period for filling a paddy field is about 150 days in Japan. The PEC is evaluated in order to compare it with the regulatory withholding standard concerning water pollution (cut-off criteria level). The cut-off criteria level is established on the basis of the ADI of the active ingredient concerned. If the PEC exceeds the cut-off criteria level, the registration of the pesticide is withheld and ariskmitigation measure, such as a reduction in the application rate or an establishment of a flow-out stopping time of paddy water has to be considered. As mentioned above, for spray drift, PEC is not calculated in Japan, however, this exposure route is qualitatively taken into account and, when necessary, a risk mitigation measure is taken by the description of the precaution on the label. For risk mitigation at the post-registration stage, the following measures are taken when necessary: The Standards for Safe Use of Agricultural Chemicals Concerning Prevention of Water Pollution (8) provides that users of the pesticides,



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for which the Environmental Quality Standards for Water Pollution (9) are established, shall pay attention not to allow pesticide spray to drift overriversand where water purification plants are located. The Standards for Safe Use of Agricultural Chemicals Concerning Aerial Application (70) provides that the aerial application shall not be carried out in areas whereriversand water purification plants are located. A pesticide that may cause water pollution in a public water area and, consequently, may cause damage to man and livestock when used in large quantities in extensive areas, may be designated by the Government as an agricultural chemical that causes water pollution. For a pesticide so designated, the Prefectural authorities may determine the area, when necessary, where any user of the pesticide shall not use the pesticide without obtaining a permit in advance from the Prefectural authorities. Assessment and Mitigation of Risk to Aquatic Organisms. The L C of common carp (48hrs) and LC50 of Daphnia (3hrs) are used for the assessment. The cut-off criteria level is established on the basis of the L C of common carp (48hrs). This cut-off criteria does not consider the PEC. However, for pesticides that do not exceed the cut-off criteria, a risk assessment is conducted that takes into consideration the PEC. In this case, the PEC is calculated from direct overspray to a body of water with a depth of 5 cm. According to the result of the risk assessment, a risk mitigation measure is taken. For spray drift, the PEC is not calculated in Japan; however, this exposure route is qualitatively taken into account and, when necessary, a risk mitigation measure is taken (e.g., the precaution on the label). As one measure of risk mitigation, precautions for the users are described on the label. An example of a precaution is "This pesticide may cause damage to fish and crustaceans and may not be used near nurseries of fish and crustaceans". For risk mitigation at the post-registration stage, the following measures can be conducted when necessary: the Standards for Safe Use of Agricultural Chemicals Concerning Prevention of Damage to Aquatic Animals (77) provides that users of the pesticides designated by this Direction shall pay attention to assure no drift of the applied pesticide overrivers,lakes, ponds, etc. A pesticide that possesses the potential for serious damage to aquatic animals and plants when used in large quantities in extensive areas may be designated as an agricultural chemical that causes water pollution by the government. For such designated pesticides, the Prefectural authorities may determine the area, when necessary, where any user of the pesticide shall not use the pesticide without obtaining a permit in advance from the Prefectural authorities. 50

50

Literature Cited 1. Good Laboratory Practice for NonclinicalLaboratoryStudies; Food and Drug Administration; Code of Federal Regulation No. 21, Part 58; U.S.A: 1979. 2.OECDPrinciples of Good Laboratory Practices; C (81) 30 (Final) Annex; OECD: Paris, 1981.



277 3. Good Laboratory Practice Standards for Toxicological Studies on Agricultural Chemicals; Director-General of Agricultural Production Bureau, Ministry of Agriculture Forestry and Fisheries; 59 Nosan No. 3850; Japan: 1984. (in Japanese). 4. Agricultural Chemicals Regulation Law; Ministry of Agriculture, Forestry and Fisheries; Law No. 82; Japan: 1984. (in Japanese). 5. Poisonous and Deleterious Substances Control Law; Ministry of Health and Welfare; Law No. 303; Japan: 1950. (in Japanese). 6. Food Sanitation Law; Ministry of Health and Welfare; Law No. 233; Japan: 1947. (in Japanese). 7. Standards for Withholding Agricultural Chemicals Registration; Director-General of Environmental Agency; Ministerial Notification No. 37; Japan: 1978. (in Japanese). 8. Standards for Safe Use of Agricultural Chemicals Concerning Prevention of Water Pollution; Minister of Ministry of Agriculture, Forestry and Fisheries; Announcement 6 Nosan No. 1623; Japan: 1994. (in Japanese). 9. Environmental Quality Standards Regarding Water Pollution for Protection of Human Health; Director-General of Environmental Agency; Ministerial Notification No. 16; Japan: 1993. (in Japanese). 10. Standards for Safe Use of Agricultural Chemicals Concerning Aerial Application; Minister of Ministry of Agriculture, Forestry and Fisheries; Announcement 6 Nosan No. 1623; Japan: 1994. (in Japanese). 11. Standards for Safe Use of Agricultural Chemicals Concerning Prevention of Damage to Aquatic Animals; Minister of Ministry of Agriculture, Forestry and Fisheries; Announcement 6 Nosan No. 1623; Japan: 1994. (in Japanese).


Good Laboratory Practices and Pesticide Regulation in Japan - ACS

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